Mitotax^® (Concentrate) Instructions for Use

Marketing Authorization Holder

Dr. Reddy’s Laboratories Ltd. (India)

Labeled By

Dr. Reddy`s Laboratories, Ltd. (India)

Contact Information

Dr. Reddy`s Laboratories Ltd. (India)

ATC Code

L01CD01 (Paclitaxel)

Active Substance

Paclitaxel (Rec.INN)

Dosage Forms

	Mitotax®	Concentrate for solution for infusion 30 mg/5 ml: 1 vial.
		Concentrate for solution for infusion 100 mg/16.7 ml: 1 vial.
		Concentrate for solution for infusion 250 mg/41.7 ml: 1 vial.
		Concentrate for solution for infusion 300 mg/50 ml: 1 vial.

Dosage Form, Packaging, and Composition

Concentrate for solution for infusion is a clear, colorless or pale yellow, slightly viscous liquid.

Excipients: macrogol glycerol hydroxystearate, ethanol, citric acid.

5 ml – colorless glass vials (1) – cardboard packs.

Concentrate for solution for infusion is a clear, colorless or pale yellow, slightly viscous liquid.

Excipients: macrogol glycerol hydroxystearate, ethanol, citric acid.

16.7 ml – colorless glass vials (1) – cardboard packs.

Concentrate for solution for infusion is a clear, colorless or pale yellow, slightly viscous liquid.

Excipients: macrogol glycerol hydroxystearate, ethanol, citric acid.

41.7 ml – colorless glass vials (1) – cardboard packs.

Concentrate for solution for infusion is a clear, colorless or pale yellow, slightly viscous liquid.

Excipients: macrogol glycerol hydroxystearate, ethanol, citric acid.

50 ml – colorless glass vials (1) – cardboard packs.

Clinical-Pharmacological Group

Antineoplastic drug

Pharmacotherapeutic Group

Antineoplastic agent – alkaloid

Pharmacological Action

An antineoplastic drug of plant origin, obtained semi-synthetically from the plant Taxus Baccata.

The mechanism of action is associated with the ability to stimulate the “assembly” of microtubules from dimeric tubulin molecules, stabilize their structure by preventing depolymerization, and inhibit dynamic reorganization in the interphase, which disrupts the mitotic function of the cell.

In addition, Paclitaxel induces the formation of abnormal clusters or “bundles” of microtubules throughout the cell cycle and multiple star-shaped clusters (asters) during mitosis.

It causes a dose-dependent suppression of bone marrow hematopoiesis.

Experimental studies have established that the drug has mutagenic and embryotoxic properties and causes a decrease in reproductive function.

Pharmacokinetics

With intravenous infusion over 3 hours at a dose of 135 mg/m², C_max is 2170 ng/ml, AUC is 7952 ng/h/ml; with the same dose administered over 24 hours – 195 ng/ml and 6300 ng/h/ml, respectively.

C_max and AUC are dose-dependent: with a 3-hour infusion, an increase in dose to 175 mg/m² leads to an increase in these parameters by 68% and 89%, and with a 24-hour administration – by 87% and 26%, respectively.

Plasma protein binding is 88-98%. The half-life of distribution from blood to tissues is 30 minutes. It easily penetrates tissues, accumulating mainly in the liver, spleen, pancreas, stomach, intestines, heart, and muscles.

It is metabolized in the liver by hydroxylation involving cytochrome P450 isoenzymes CYP2D8 (forming the metabolite 6-alpha-hydroxypaclitaxel) and CYP3CA4 (forming metabolites 3-para-hydroxypaclitaxel and 6-alpha, 3-para-dihydroxypaclitaxel).

T_1/2 and total clearance are variable and depend on the dose and duration of intravenous administration: 13.1-52.7 hours and 12.2-23.8 l/h/m², respectively. 90% of the drug is excreted in the bile as metabolites. A small amount (from 1.3% to 12.6%, depending on the administered dose level) is excreted unchanged in the urine.

Indications

• Ovarian cancer (first-line therapy for patients with advanced disease or residual tumor (more than 1 cm) after laparotomy (in combination with cisplatin) and second-line therapy for metastases after standard therapy that did not yield a positive result);
• Breast cancer (involvement of lymph nodes after standard combination therapy (adjuvant treatment); after disease recurrence within 6 months of starting adjuvant therapy – first-line therapy; metastatic breast cancer after ineffective standard therapy – second-line therapy);
• Non-small cell lung cancer (first-line therapy for patients not planned for surgical treatment and/or radiation therapy – in combination with cisplatin).

ICD codes

Dosage Regimen

To prevent the development of severe allergic reactions, all patients should receive premedication with corticosteroids, antihistamines (including histamine H₂-receptor antagonists) before starting the infusion: 20 mg dexamethasone (or its equivalent) orally or intramuscularly 12 hours and 6 hours before administration of Mitotax^®, 50 mg diphenhydramine (or its equivalent) intravenously and 300 mg cimetidine or 50 mg ranitidine intravenously 30-60 minutes before administration of Mitotax^®.

When choosing the regimen and doses in each individual case, one should be guided by data from specialized literature.

Mitotax^® is administered intravenously as a 3-hour or 24-hour infusion at a dose of 175 mg/m² or 135 mg/m² respectively, with an interval between administrations of 3 weeks. The drug is used as monotherapy or in combination with cisplatin (for ovarian cancer and non-small cell lung cancer) or doxorubicin (for breast cancer).

Repeated administrations of Mitotax^® are carried out when the neutrophil count in peripheral blood is ≥1500/µl and platelets ≥100,000/µl.

For patients who experienced severe neutropenia (neutrophil count <500/µl of blood for 7 days or longer) or severe peripheral neuropathy after previous administrations of paclitaxel, the dose of Mitotax^® should be reduced by 20% during subsequent courses of treatment.

Rules for preparation, administration and storage of the solution

The solution for infusion is prepared immediately before administration.

The concentrate is diluted with 0.9% sodium chloride solution, 5% dextrose solution, or a combination of 5% dextrose solution with 0.9% sodium chloride solution, or a combination of 5% dextrose solution in Ringer’s solution. The final concentration of paclitaxel in the solution should be from 0.3 to 1.2 mg/ml. The prepared solutions may appear opalescent due to the carrier base present in the drug formulation, and the opalescence of the solution may persist after filtration.

When preparing, storing, and administering Mitotax^®, equipment that does not contain PVC parts should be used.

Solutions of Mitotax^® should be prepared and stored in glass, polypropylene, or polyolefin systems and administered through infusion systems with an internal polyethylene surface, as well as through a membrane filter connected to the system with a pore size of no more than 0.22 microns.

Adverse Reactions

The frequency and severity of side effects are dose-dependent.

From the hematopoietic system: neutropenia, thrombocytopenia, anemia. Suppression of bone marrow function, mainly the granulocytic lineage, was the main toxic effect limiting the dose of the drug. The maximum decrease in neutrophil levels is usually observed on days 8-11, with normalization occurring on day 22.

Allergic reactions: skin rash, flushing of the skin of the face and upper chest, angioedema, bronchospasm, generalized urticaria, decreased blood pressure, chest pain. Isolated cases of chills and back pain have been described.

From the cardiovascular system: decreased blood pressure, less commonly – increased blood pressure, bradycardia or tachycardia, arrhythmia, AV block, ventricular bigeminy, ECG changes, venous thrombosis.

From the respiratory system: interstitial pneumonia, pulmonary fibrosis, pulmonary embolism, as well as more frequent development of radiation pneumonitis in patients simultaneously undergoing a course of radiation therapy.

From the nervous system: peripheral neuropathy (mainly paresthesia); rarely – grand mal seizures, ataxia, encephalopathy, optic nerve damage, autonomic neuropathy manifested as paralytic ileus and orthostatic hypotension.

From the musculoskeletal system: arthralgia, myalgia.

From the digestive system: nausea, vomiting, diarrhea, mucositis, anorexia, constipation; there are isolated reports of acute intestinal obstruction, intestinal perforation, mesenteric artery thrombosis, ischemic colitis; increased activity of liver transaminases (more often AST), alkaline phosphatase and bilirubin in blood serum. Cases of hepatonecrosis and hepatic encephalopathy have been described.

Dermatological reactions: alopecia, rarely – pigmentation disorder or discoloration of the nail bed.

From the sensory organs: decreased visual acuity, conjunctivitis, increased lacrimation.

Local reactions: thrombophlebitis, pain, swelling, erythema, induration and skin pigmentation at the injection site; extravasation can cause inflammation and necrosis of the subcutaneous tissue.

Other: asthenia and general malaise, decreased tolerance to infections (of any etiology).

Contraindications

• Baseline neutrophil count less than 1500/µl;
• Pregnancy;
• Period of lactation (breastfeeding);
• Hypersensitivity to paclitaxel or other components of the drug (including polyoxyl castor oil).

With caution the drug should be prescribed for thrombocytopenia (less than 100,000/µl), hepatic insufficiency, acute infectious diseases (including herpes zoster, chickenpox, herpes), severe coronary artery disease, myocardial infarction (in history), arrhythmias.

Use in Pregnancy and Lactation

The drug is contraindicated during pregnancy and breastfeeding.

Patients should use reliable methods of contraception during treatment with Mitotax^® and for at least 3 months after the end of therapy.

Use in Hepatic Impairment

With caution the drug should be prescribed for hepatic insufficiency.

Pediatric Use

The safety and efficacy of paclitaxel in children have not been established.

Special Precautions

Treatment with Mitotax^® should be carried out under the supervision of a physician experienced in working with antineoplastic chemotherapeutic drugs.

If Mitotax^® is used in combination with cisplatin, Mitotax^® should be administered first, followed by cisplatin.

During treatment, it is necessary to regularly monitor the peripheral blood count, blood pressure, heart rate and respiratory rate (especially during the first hour of infusion), ECG monitoring (including before starting treatment).

In case of development of severe hypersensitivity reactions, the infusion of Mitotax^® should be immediately stopped and symptomatic treatment started, and the drug should not be re-administered.

In cases of development of AV conduction disturbances, continuous cardiac monitoring should be performed during repeated administrations.

Mitotax^® is a cytotoxic substance, and caution must be exercised when handling it, using gloves and avoiding contact with skin or mucous membranes, which in such cases should be thoroughly washed with soap and water, or (eyes) with plenty of water.

Use in pediatrics

The safety and efficacy of paclitaxel in children have not been established.

Effect on ability to drive vehicles and operate machinery

During the treatment period, caution should be exercised when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

Symptoms bone marrow aplasia, peripheral neuropathy, mucositis.

Treatment symptomatic. An antidote to paclitaxel is not known.

Drug Interactions

Cisplatin reduces the total clearance of paclitaxel by 20% (with more pronounced myelosuppression observed when Paclitaxel is administered after cisplatin).

Microsomal oxidation inhibitors (including ketoconazole, verapamil, diazepam, quinidine, cyclosporine) suppress the metabolism of paclitaxel.

Concomitant use with cimetidine, ranitidine, dexamethasone, or diphenhydramine does not affect the binding of paclitaxel to plasma proteins.

Polyoxyl castor oil, which is part of paclitaxel, can cause extraction of DEHP (di-(2-ethylhexyl) phthalate) from plasticized polyvinyl chloride containers, and the degree of DEHP leaching increases with increasing solution concentration and over time.

Storage Conditions

List B. The drug should be stored in a dry, light-protected place, out of reach of children, at a temperature not exceeding 25°C (77°F); do not freeze.

Shelf Life

The shelf life is 2 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.